Gary Levy, MD
Karen Purcell, MD, PhD
OVARIAN CANCER
ESSENTIALS OF DIAGNOSIS
Early-stage ovarian cancer often presents with vague and ill-defined symptoms.
Late-stage disease presents with abdominal pain or bloating, early satiety, and/or urinary urgency or frequency.
The majority of women present with late-stage disease.
Pelvic ultrasound findings show complex adnexal mass(es).
The mean age of diagnosis for epithelial ovarian cancer is in the mid-50s, with the majority diagnosed between ages 40 and 65.
Hereditary causes of ovarian cancer diagnosed at earlier age by almost a decade.
Nonepithelial ovarian tumors are more common in girls and younger women.
Pathogenesis
Although there are many different cell types present in the normal adnexa, the majority of adnexal cancers arise from the surface epithelial cells of the ovary (epithelial ovarian cancer [EOC]). Fewer ovarian cancers develop from the remaining cell types (sex cord-stromal, germ cell, or mixed cell type tumors) (Table 50–1), and even fewer adnexal cancers arise from the fallopian tubes, although recent evidence has shown that they account for a greater percentage than previously thought. The specific events leading to the transition of normal tissue to malignancy have not been established, nor has a definitive precursor lesion been identified. For sporadic tumors, molecular events leading to the inactivation of tumor suppressor genes (PTEN, p16, p53) or the activation of oncogenes (HER-2, c-myc, K-ras, Akt) have been described. For the small proportion of genetically heritable cancers, germline mutations in BRCA1, BRCA2, and other genes have been described, but the molecular pathway leading to tumorigenesis has not been elucidated. It is likely that epigenetic events also contribute to the transformation to cancer.
Table 50–1. Categories of ovarian cancer.
A. Epithelial Ovarian Cancer
The most prominent theory for the development of EOC associates the repeated trauma and repair to the ovarian epithelium during normal ovulation with subsequent genetic alterations and further progression to malignant transformation. This is supported by evidence that suppression of ovulation leads to a decreased incidence of EOC. A second theory invokes high serum concentrations of gonadotropins, estrogen, androgen, or inflammatory agents, leading to epithelial proliferation and subsequent transformation.
EOCs account for more than 90% of all malignant ovarian tumors and include serous, mucinous, endometrioid, clear cell, transitional cell types, and undifferentiated neoplasms. Serous cystadenocarcinomas represent 75–80% of EOCs. They present with extraovarian spread 85% of the time and are bilateral in half the cases. The tumors are typically large at the time of diagnosis, most being larger than 15 cm in diameter, with the unilocular or multilocular cystic structures containing papillae projecting into the lumen. Histologic sections resemble the endosalpinx with nuclear atypia in the stratified squamous epithelium. Psammoma bodies with irregular lamellar calcifications are frequently seen in these tumors. The grade of differentiation is based on the degree of preservation of the papillary architecture, the majority of which is poorly differentiated at the time of diagnosis.
Mucinous cystadenocarcinomas represent 10% of all EOCs, are typically unilateral, and are notable for the ability to attain very large sizes. Histologic sections resemble endocervical epithelium with large hyperchromatic nuclei and prominent nucleoli. The variability within the tumor requires extensive sampling to determine the most malignant focus. Given the similar cell architecture, they are often difficult to distinguish from metastatic tumors from the colon, appendix, endocervix, and pancreas. Thus after diagnosis of a mucinous tumor, an evaluation of the gastrointestinal (GI) tract is recommended.
Mucinous tumors, whether from ovarian origin or appendix, can be associated with a condition called pseudomyxoma peritonei where progressive accumulation of mucin within the abdominal cavity occurs and often leads to significant protracted morbidity secondary to bowel obstruction.
Endometrioid neoplasms of the ovary occur bilaterally in 30–50% of cases and account for 10% of EOCs. Histologic sections reveal an adenomatoid pattern with the degree of differentiation determined by the extent to which the glandular architecture is preserved. Rarely, this tumor arises within a focus of endometriosis, but not uncommonly, patients with endometrioid tumors of the ovary will have a synchronous endometrial carcinoma.
Clear cell carcinoma of the ovary, or mesonephroid carcinoma, accounts for <1% of EOCs. They typically present at a smaller size than the serous or mucinous cyst-adenocarcinomas. These tumors are aggressive and may be associated with hypercalcemia or hyperpyrexia. Histologic sections show features of “clear cells,” similar to renal cell carcinomas; occasionally, they are difficult to differentiate from mucinous neoplasms, although a weak staining pattern with the periodic acid-Schiff reaction is useful.
Transitional cell carcinoma, or Brenner’s tumor, accounts for <1% of EOCs. Histologic sections resemble low-grade transitional cell carcinoma of the urinary bladder. Compared to other types of EOCs, these patients have a poorer prognosis.
Undifferentiated carcinomas account for <10% of EOCs and are characterized by the absence of any microscopic features to define them as another type.
B. Germ Cell Tumors of the Ovary
Although EOCs typically occur in women near or in menopause, germ cell tumors tend to present in the second and third decades of life. Also different from EOCs, these tumors often have a good prognosis. Because they arise from the germ cell elements of the ovary, they often secrete hormones or proteins that can be used to monitor response to therapy (Table 50–2).
Table 50–2. Biologic markers associated with ovarian tumors.
Dysgerminomas account for 30–40% of the germ cell tumors. They occur in young females and most often are unilateral at presentation. Although they are solid tumors, they may have areas of softening due to degeneration. At the time of surgery, they appear smooth and thinly encapsulated, with a brown or grayish-brown color. On histologic sections, nests of germ cells, which appear as large, rounded cells with central nuclei, are surrounded by undifferentiated stroma. If lymphocytic infiltration is present, it is considered a favorable prognostic indicator.
Immature teratomas are the malignant counterpart of mature cystic teratomas, or dermoids, and are the second most common germ cell malignancy. Histologic sections show a disordered collection of tissues derived from all 3 germ layers, with some components having an immature, embryonic appearance. The grade of the tumor is determined by the amount of immature neural tissue present, which correlated with prognosis and guidelines for chemotherapy. Typical presentation occurs in females <20 years old. They are usually unilateral, although the contralateral ovary may contain a mature teratoma. These tumors often secrete α fetoprotein (AFP).
Endodermal sinus tumors, or yolk sac tumors, are the third most common germ cell tumor. This is the most rapidly growing neoplasm that occurs at any site, and patients may present with an acute abdomen given they are friable, necrotic, and often hemorrhagic. These tumors are almost always bilateral and, on histologic section, resemble the primitive gut and liver; Schiller-Duval bodies, which show a single papilla lined by tumor cells with a central blood vessel, and the production of AFP are characteristic.
Embryonal carcinoma presents at a mean age of 15 years old and has a highly aggressive growth pattern. Histologic sections show solid sheets of large polygonal cells with pale, eosinophilic cytoplasm that give the appearance of a syncytium. Biologic markers of AFP, human chorionic gonadotropin (hCG), and estrogens are often secreted.
Choriocarcinoma of the ovary is a rare germ cell tumor. Unlike gestational choriocarcinoma, this primary ovarian tumor produces lower levels of hCG and may cause precocious puberty, uterine bleeding, or amenorrhea. Histologic sections show cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblasts.
Gonadoblastoma is a rare germ cell tumor that presents in the second decade of life and is located more commonly in the right ovary over the left. Patients have abnormal gonadal development with the presence of a Y chromosome. Histologic sections show nests of germ cells and sex cord derivatives surrounded by connective tissue stroma.
Mixed germ cell tumors account for 10% of germ cell neoplasms and contain 2 or more germ cell elements. The most frequent composition includes dysgerminoma and endodermal sinus tumor. Careful sectioning by the pathologist is necessary to determine all different components in order to correctly determine the chemotherapeutic regimens.
Polyembryoma is extremely rare and is seen in premenarchal girls with signs of pseudopuberty. It secretes AFP and hCG and histologically will contain the 3 somatic layers of early embryonic differentiation.
C. Sex Cord-Stromal Tumors of the Ovary
Sex cord-stromal tumors of the ovary account for 5–8% of all ovarian malignancies. Granulosa cell tumors account for 70% of this class of tumors. Because they secrete high levels of estrogen, they may cause precocious puberty in young girls or adenomatous hyperplasia and vaginal bleeding in postmenopausal women. Microscopically, the granulosa cells exhibit characteristic grooved or coffee bean nuclei; Call-Exner bodies represent multiple small cavities that contain eosinophilic fluid. Theca cells are present in varying amounts. Granulosa cell tumors are characterized by inhibin secretion, and this tumor marker can be used for monitoring tumor progression and response to therapy.
Like granulosa cell tumors, ovarian thecomas are associated with hyperestrogenism. This mostly benign ovarian tumor consists of lipid-laden stromal cells, which confer a yellow appearance on cut section.
Sertoli-stromal cell tumors are rare, consisting of testicular structures at different stages of development and therefore are usually virilizing. The average age at diagnosis is 25, and they are rarely bilateral. Microscopically, both Sertoli and Leydig cells are present. A variety of architectural patterns have been described.
D. Borderline Tumors of the Ovary
For 10% of women with malignant ovarian neoplasms, the histologic pattern shows atypical epithelial proliferation without stromal invasion. These tumors are termed serous tumors of low malignant potential (LMP) or noninvasive borderline tumors. They tend to have similar genetic alterations and molecular pathways to low-grade carcinomas, which are different from those seen with high-grade serous carcinomas. Although this has led some to hypothesize that the borderline tumors and low-grade carcinomas are a part of a progression to high-grade carcinomas, most believe they are 2 separate entities rather than a continuum of tumor progression often seen with other gynecologic malignancies. There is no evidence that low-grade serous carcinomas arise from serous tumors of LMP.
E. Metastatic Disease to the Ovary
Approximately 5% of ovarian tumors are due to metastases, with the primary tumor being located in the female genital tract, breast, or gastrointestinal tract. Traditionally, Krukenberg tumors signaled metastases from the stomach, although now the term is used more loosely to define ovarian tumors from any location in the gastrointestinal tract.
F. Hereditary Ovarian Cancer Syndromes
Although the majority of ovarian cancers are defined as sporadic, approximately 10–15% of cases are attributed to genetic causes. Breast–ovarian cancer syndrome is one such cause, with the majority of patients having mutations in BRCA1 or BRCA2. Germline mutations in BRCA1 confer a 35–45% lifetime risk of ovarian cancer, whereas BRCA2 mutations confer a 15–24% risk of ovarian cancer. Within the United States, approximately 1 in 800 women are carriers, and this rate is increased for women of Ashkenazi Jewish, French Canadian, or Icelandic descent.
A second syndrome is Lynch II syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC). These women have a 12% risk of developing ovarian cancer and are also at increased risk of developing cancers of the colon, breast, and endometrium. Several gene mutations have been detected in families with Lynch II, including PMS1, PMS2, MSH2, MSH3, MSH6, and MLH1. Each of these is known to be involved in DNA mismatch repair.
G. Cancer of the Fallopian Tubes
Primary carcinoma of the fallopian tube is the least common cancer arising in the female genital tract, accounting for approximately 0.3% of all such cancers. Fallopian tube cancers are similar to EOC with regard to clinical presentation and biologic behavior. At least 95% of all primary carcinomas of the fallopian tube are papillary carcinomas. Bilaterality is found in 40–50% of cases, and this is believed to represent synchronous neoplasms rather than metastatic disease from one tube to the other. Grossly, the affected tube is fusiform or sausage-shaped. On initial inspection, these neoplasms resemble pyosalpinx or tubo-ovarian inflammatory disease. However, there is usually little associated serosal reaction with adhesion formation, as is noted with an inflammatory process.
Classically, the neoplastic fallopian tube contains solid or necrotic cancer tissue and a dark-brown or serosanguinous fluid. The fimbriated end of the fallopian tube is patent in as many as 50% of cases, and often tumor extrudes from the ostium to adhere to adjacent structures. Histologically, papillary carcinomas may exhibit papillary, papillary–alveolar, and alveolar growth patterns. There is no prognostic significance attached to these differences. Of note, women with BRCA1 and BRCA2 mutations are at substantially higher risk of fallopian tube cancer; consequently, women who have prophylactic oophorectomies should also have complete resection of the oviducts.
de Waal YR, Thomas CM, Oei AL, Sweep FC, Massuger LF. Secondary ovarian malignancies: frequency, origin, and characteristics. Int J Gynecol Cancer 2009;19:1160. PMID: 19823050.
Lalwani N, Shanbhogue AK, Vikram R, et al. Current update on borderline ovarian neoplasms. AJR Am J Roentgenol 2010; 194:330. PMID: 20093592.
Roett MA, Evans P. Ovarian cancer: an overview. Am Fam Physician 2009;80:609. PMID: 19817326.
Shih IM, Davidson B. Pathogenesis of ovarian cancer: clues from selected overexpressed genes. Future Oncol 2009;5:1641. PMID: 20001801.
Prevention
The lifetime risk of ovarian cancer in the general population is 1.7%, and the majority of known risks factors are not amenable to change, with age, early menarche (prior to age 12), and late menopause (after age 50) being the most prominent. Ethnic differences confer variable risk. Caucasians have the highest age-adjusted annual incidence per 100,000 women in the United States with a rate of 14.3. Hispanics are less, at 11.5, then African-Americans at 10.1 and Asians at 9.7. Infertility is also a risk factor, whereas fertility treatment is unlikely to be a risk factor. Endometriosis is an independent risk factor of EOC; malignant transformation occurs in approximately 2.5% of patients, who are typically younger. The prognosis is typically better because the tumors are more often well-differentiated, low-stage carcinomas. Nulligravidity is a major risk factor for EOC.
Certain protective factors have been identified. The use of oral contraceptive pills (OCPs) decreased the risk of ovarian cancer, with increasing protection conferred by longer duration of use. The risk is reduced to half by 15 years of use, and the protection persists after discontinuing medication, although the effects become attenuated over time. Low-dose OCPs, with ≤ 35 μg of ethinyl estradiol are as effective as the higher dose OCPs. Women who have undergone tubal ligation were found to have a decreased risk by about a third to a half, with the effect being synergistic with a history of OCP use. However, caution must be taken when suggesting this as a preventive measure, especially in patients with hereditary syndromes because occult malignancies within the fallopian tubes are often present in women carrying a genetic mutation. Breastfeeding and progesterone use have also been shown to have a protective effect.
One environmental factor, current or past cigarette smoking, is known to increase the risk of mucinous ovarian cancer but not other types of EOC. The contribution of diet is uncertain, as most published studies have potential biases. The effects of exercise are also without a clear relationship to the risk of ovarian cancer. Obesity may lead to an increased risk of ovarian cancer. Previous studies had implicated talc use as leading to a small increased risk of ovarian cancer, although recent studies have not substantiated this.
Prevention by screening methods is currently not possible. The lack of sensitivity or specificity of available testing negates their use to identify women at risk of developing ovarian cancer, and therefore, screening by any modality is not recommended.
Risk Reduction in Women with Familial Ovarian Cancer Syndromes
One of the strongest known risk factors for ovarian cancer is a family history of the disease. A family pedigree of at least 3 generations should be evaluated by a geneticist to provide counseling and consent for potential genetic testing. Although a woman with a family history of ovarian cancer has an increased personal lifetime risk of 2–6%, women with a familial ovarian cancer syndrome are at significantly greater lifetime risk of 25–50%.
Efforts to find effective screening, through use of ultrasound or multimodal techniques encompassing humoral markers, have been disappointing. Thus prophylactic bilateral salpingo-oophorectomy (BSO) has been advocated to reduce the risk for patients with a familial ovarian cancer syndrome. This procedure leads to a significant reduction in the risk of ovarian cancer (80–90% for BRCA carriers) as well as decreased overall mortality; however, the gains in life expectancy are dependent on the age at the time of the procedure, with little gain for women undergoing the procedure after the age of 60. The decision to proceed with prophylactic BSO requires a careful discussion of consequences of infertility and premature menopause. Most suggest performing the procedure as soon as childbearing is complete or by age 35.
An alternative preventive measure may be the use of OCPs containing a high-potency progestin. Although results have been mixed, the majority show an appropriate reduction in risk of ovarian cancer in these women.
Mourits MJ, de Bock GH. Managing hereditary ovarian cancer. Maturitas 2009;64:172. PMID: 19811881.
Clinical Findings
A. Symptoms & Signs
Early-stage EOC is associated with poorly defined or vague symptoms, which often are not severe enough to prompt a woman to seek medical attention. For later stage disease, which accounts for more than 70% of all diagnoses, the most common symptoms include an increased abdominal girth, pelvic or abdominal pain, bloating, urinary symptoms of frequency or urgency, or early satiety. Occasionally patients will have nausea or anorexia secondary to ascites or bowel metastases. Patients may also present with dyspnea due to pleural effusions. Rarely do patients present with paraneoplastic phenomena such as subacute cerebellar degeneration, seborrheic keratoses (sign of Leser-Trelat), Trousseau’s syndrome (migratory thrombophlebitis), or hypercalcemia of malignancy.
Approximately 15% of reproductive-age patients will present with menstrual abnormalities. Abnormal vaginal bleeding may occur in the presence of a synchronous endometrial carcinoma or as a consequence of metastatic disease to the lower genital tract. Excess androgens or estrogens may be present due to stimulation of normal theca, granulosa, or hilar cells that surround the neoplasm or due to secretion by a germ cell tumor or sex cord-stromal tumor. Ovarian stromal hyperplasia or hyperthecosis may also be associated with excess androgen production.
A pelvic exam will often reveal a solid, fixed, irregular adnexal mass. Unilateral, cystic masses in reproductive-age women are benign in up to 95% of cases. These masses, particularly when <6–8 cm in size, are observed through a menstrual cycle because many represent functional cysts that spontaneously resolve. An enlarging mass or one that is associated with pain merits prompt intervention. A cystic, somewhat immobile adnexal mass may represent a hydrosalpinx or tubo-ovarian abscess. Fixed, bilateral masses and firm masses with nodularity are suggestive of, but not diagnostic of, an ovarian malignancy (Table 50–3).
Table 50–3. Characteristics to be noted on physical exam of a pelvic mass.
Although several benign lesions may also present with similar findings, the presence of ascites or an upper abdominal mass are very suggestive of ovarian cancer. Abdominal distention is one of the more common findings. The presence of flank fullness and shifting dullness implies the presence of ascites or a large pelvic-abdominal mass. Together with these signs, tympanitic percussion noted over the lateral abdomen is consistent with a large mass that displaces the bowel to the periphery. In contrast, a central tympanitic percussion note is suggestive of ascites. Recent eversion of the umbilicus in a patient with abdominal distention may result from an increase in intraabdominal pressure secondary to ascites.
A rectal exam evaluating the presence of occult blood in the stool should also be performed given the possibility of a primary gastrointestinal malignancy with metastases to the ovary. Similarly, a breast exam should be performed, and the presence of a breast mass warrants a mammogram, given the possibility of a primary breast cancer with ovarian metastases. Particular attention should be paid to the lymph node–bearing areas, particularly the supraclavicular and inguinal areas. Metastatic disease to the skin rarely occurs in the presence of ovarian cancer. Sister Mary Joseph’s nodule refers to a metastatic implant in the umbilicus.
For patients with carcinoma of the fallopian tube, presentation typically occurs in the fifth or sixth decade of life, and the signs and symptoms are often similar to those noted in patients with ovarian cancer. In fact, it is difficult to differentiate tubal from ovarian carcinomas preoperatively. Fewer than 15% of patients are noted to have the classic triad of symptoms and signs associated with fallopian tube cancer including hydrops tubae profluens (a watery vaginal discharge), pelvic pain, and a palpable adnexal mass. Positive vaginal cytology in the absence of endometrial or cervical neoplasia suggests the possibility of a tubal cancer, but this is rarely diagnostic.
B. Laboratory Findings
The best characterized tumor marker in EOC is cancer antigen-125 (CA-125). CA-125 is a secreted glycoprotein present in fetal amniotic and coelomic epithelium, and its level can be detected in serum using immunoassay. The accepted upper limit of normal is 35 IU/mL, but this is a rather arbitrary cutoff. CA-125 is elevated in many patients with ovarian cancer, especially with serous histology, but is also elevated in other malignancies such as pancreatic, colon, breast, stomach, fallopian, or endometrial cancer. In addition, it is also elevated in certain benign conditions such as endometriosis, leiomyoma, or pelvic inflammatory disease, although rarely above 200 IU/mL. Therefore, it can be a useful adjunct in postmenopausal women, but not very useful in premenopausal women given the low incidence of EOC and greater incidence of benign lesions. Additionally, a normal CA-125 does not exclude the diagnosis of cancer and does not represent a reason to delay surgery.
In young girls and adolescents presenting with an adnexal mass, serum AFP, lactate dehydrogenase (LDH), and hCG should be measured as potential biomarkers given the greater likelihood of a malignant germ cell tumor.
In all patients, a complete blood count (CBC), serum electrolyte test, and hCG level should be drawn. For patients with apparent ascites, a paracentesis is not advocated as a routine procedure once renal, cardiac, and hepatic failure have been excluded. False-negative results may occur in as many as 40% of patients with widespread intraabdominal disease. In contrast to paracentesis, diagnostic thoracentesis for cytology is recommended for staging purposes; the presence of a malignant pleural effusion confirms stage IV disease.
C. Imaging Studies
Pelvic ultrasound helps delineate the presence of a benign or malignant adnexal mass (Table 50–4), and a number of different scoring systems have been used, although there is no standardized system for evaluation of ovarian masses. Typical characteristics of ovarian cancer include a solid component, which is often nodular or papillary, septations, and ascites. Angiogenesis accompanying malignancy results in vascular abnormalities and increased blood flow compared with the vascular architecture and patterns of blood flow in nonmalignant lesions. The addition of color flow Doppler studies that evaluate the vascular patterns of adnexal masses improves the sensitivity and specificity of the radiographic diagnosis of benign and malignant lesions. However, even when combined with laboratory or physical findings, ultrasound is limited in making a definitive diagnosis, and surgery is required to document malignancy histologically.
Table 50–4. Ultrasonographic features to aid diagnosis of benign and malignant adnexal masses.
Characterization of adnexal masses by computed tomography (CT) or magnetic resonance imaging (MRI) may provide clinically useful information in select instances. CT scanning provides information about the retroperitoneal structures in addition to the pelvic organs. MRI scans can add more information regarding the nature of the ovarian neoplasm. Because of the high cost and questionable benefit, this diagnostic procedure is infrequently used for ovarian tumors. However, it may be of particular benefit in the evaluation of pregnant patients because it avoids radiation exposure of the fetus.
A patient with suspected ovarian malignancy should undergo a radiograph of the chest to exclude metastatic parenchymal disease and to detect a pleural effusion. If the patient notes a change in bowel habits or if guaiac-positive stools are detected, a barium enema should be obtained. Patients who appear to have advanced ovarian cancer, evidenced by a nodular pelvic mass with or without ascites, may actually have colon cancer. Because of the genetic links among ovarian cancer, colon cancer, and breast cancer, a patient with a suspected ovarian malignancy should also undergo a screening mammogram study.
Twickler DM, Moschos E. Ultrasound and assessment of ovarian cancer risk. AJR Am J Roentgenol 2010;194:322. PMID: 20093591.
Differential Diagnosis
The differential diagnosis of a pelvic mass is influenced by the age of the patient, the characteristics of the mass on pelvic examination, and the radiographic appearance of the mass. In general, the prepubescent child and the postmenopausal woman are at greatest risk for a malignant ovarian neoplasm. The reproductive-age woman is more likely to have a functional ovarian cyst or endometrioma. Although functional cysts are typically mobile, both endometriomas and tubo-ovarian abscesses can present as an adnexal mass that is fixed, solid, and irregular.
Mature teratomas or dermoids are common ovarian neoplasms, occurring primarily in women ages 20–30 years. They represent the most common neoplasm diagnosed during pregnancy. Less than 1% of all teratomas are malignant.
An ovarian fibroma is another benign tumor that is noteworthy because of its association with Meigs’ syndrome. Meigs’ syndrome refers to the occurrence of an ovarian fibroma, ascites, and pleural effusion, which collectively mimic the presentation of ovarian cancer.
For masses diagnosed by ultrasound, pathologies such as pedunculated fibroids, hydrosalpinx, peritoneal inclusion cyst, and paraovarian cysts also need to be considered. Persistence of ultrasonic findings on a repeat scan after 4–6 weeks may help reduce the false-positive rate associated with ovarian masses.
Givens V, Mitchell GE, Harraway-Smith C, Reddy A, Maness DL. Diagnosis and management of adnexal masses. Am Fam Physician 2009;80:815. PMID: 19835343.
Complications
The majority of complications from ovarian cancer arise secondary to metastases. Metastases often arise from exfoliation into the peritoneal cavity and then migrate along the circulatory pattern of peritoneal fluid from the right paracolic gutter toward the upper abdomen. Additionally, hematogenous dissemination may occur. The bulk of the tumor, especially within the omentum, may lead to bowel obstruction or nutritional deficits. Removal of the mass may produce significant fluid shifts in women with advanced ovarian cancer.
Patients are at an increased risk of venous thromboembolism (VTE) if metastatic disease, medical comorbidities, or clear cell histology exist. Additionally, the first 3 months after diagnosis give rise to an increased risk of VTE. For patients undergoing surgical intervention, VTE prophylaxis is given.
Treatment
A. Surgical Intervention for Epithelial Ovarian Cancers
Surgical staging and tumor removal are required for all patients, unless the performance status of the patient limits surgical intervention. Initial surgical staging provides the definitive histologic diagnosis as well as the extent of disease. Obtaining the true stage of disease allows appropriate treatment and subsequent prognosis. Table 50–5 lists the current staging of ovarian cancer approved by the International Federation of Gynecology and Obstetrics (FIGO).
Table 50–5. International Federation of Gynecology and Obstetrics (FIGO) staging.
Intraoperatively, several features have been described that assist in the differentiation of malignant from benign adnexal masses (Table 50–6). However, gross examination of a mass is never a substitute for histologic examination. Whenever the pathology of a pelvic or adnexal mass is in question, a frozen-section pathologic study should be requested. In the hands of experienced pathologists, false-positive and false-negative diagnoses occur in <5% of cases. Patients diagnosed with ovarian cancer have to undergo surgical staging to reduce the amount of disease and evaluate the extent of spread. Removal of the primary tumor, as well as the associated metastatic disease, is referred to as tumor debulking or cytoreductive surgery. In early stages and when fertility is desired, removal of the involved adnexa alone may be considered.
Table 50–6. Intraoperative features of benign and malignant masses.
Surgical staging for ovarian cancer is performed by laparotomy. Initial recovery of ascites or pelvic free fluid is sent for cytologic evaluation. If no free fluid is present, “peritoneal washings” are obtained by instilling 50–100 cc of saline in the cul-de-sac, paracolic gutters, and underneath each hemidiaphragm. An exploratory laparotomy is then performed in a systematic and thorough manner, evaluating the pelvic organs, omentum, intestines, mesentery, gallbladder, liver, diaphragm, spleen, and entire peritoneum. The kidneys, pancreas, and lymph nodes are also evaluated in the retroperitoneum. Complete surgical staging of ovarian cancer requires the biopsy of pelvic and para-aortic lymph nodes. It is emphasized that the palpation of the retroperitoneal node-bearing areas is inaccurate and is not a substitute for biopsy and histologic examination. Table 50–7 lists the procedures included in surgical staging of ovarian cancer.
Table 50–7. Procedure to stage and remove ovarian cancer.
Removal of the tumor burden is also therapeutic. The extent of surgical resection is dependent on the stage of the disease as well as the age of the patient. If possible, complete removal of the tumor burden should be attempted as optimal cytoreduction or debulking improves subsequent systemic chemotherapy; large bulky tumors are often poorly vascularized and thus more resistant to chemotherapy and radiation therapy. Large tumor masses also consist of a higher proportion of cells in the resting phase of the cell cycle. However, even if complete resection is not possible, decreasing the tumor burden provides other benefits such as an improvement in symptoms (abdominal pain, bloating, satiety, or dyspnea) as well as a potential improvement in immune competence because ovarian tumors often produce immunosuppressive cytokines.
In general, the contralateral adnexa should be removed even when they are grossly normal. They are often the site of occult metastatic disease, and there is a significant risk of subsequent cancer. Exceptions to this generalization are made for young women with an apparent stage I epithelial ovarian neoplasm. If future fertility is desired and the patient is informed about a higher risk of recurrent disease, a more conservative surgical approach may be chosen. The histology and grade of the neoplasm, as well as the findings at the time of surgery, guide these decisions. Well-differentiated stage I lesions are associated with a much better 5-year survival rate than are moderately and poorly differentiated lesions. Mucinous and endometrioid neoplasms are associated with a better prognosis than serous and clear cell carcinomas of the ovary. If the frozen section during surgery does not reveal a reliable diagnosis of malignancy, the surgical procedure should be limited until the pathology results are finalized.
An infracolic omentectomy is recommended, even in the absence of gross tumor involvement, because it is a common site of microscopic metastatic disease. Removal of the omentum facilitates the distribution of intraperitoneal agents, may decrease the rate of accumulation of ascites postoperatively, and provides palliation to patients with omental metastases.
A hysterectomy is generally performed because the uterus is a common site for metastatic disease. There is also a risk of synchronous endometrial cancer in patients with endometrioid carcinoma of the ovary. In addition, removal of the uterus facilitates subsequent follow-up examinations and obviates potential problems secondary to uterine bleeding.
B. Surgical Intervention for Germ Cell Neoplasms
In contrast to epithelial ovarian neoplasms, most germ cell neoplasms are early stage at the time of diagnosis. This observation, in conjunction with the low incidence of bilaterality and the young age of most patients, for whom future fertility is desired, influences the surgical management of this group of neoplasms. For young women with a germ cell neoplasm of the ovary, removal of the involved adnexa with preservation of the normal-appearing contralateral adnexa and uterus is generally advocated. In view of the low incidence of bilaterality, biopsy or bivalving the contralateral ovary is not recommended because of the risk of peritubal and periovarian adhesions. Complete surgical staging of germ cell neoplasms is the same as for epithelial ovarian neoplasms and should be performed in all cases.
Certain characteristics unique to germ cell neoplasms make an impact on their surgical management. Dysgerminoma of the ovary has a propensity to metastasize to the pelvic and para-aortic lymph nodes in the absence of other evidence of metastatic disease. Performing a biopsy of these structures is particularly important. Endodermal sinus tumor of the ovary is the most rapidly growing neoplasm known to occur at any site. This diagnosis must be considered in a young woman with a rapidly enlarging pelvic or abdominal mass. Immature teratoma of the ovary may present with numerous peritoneal implants consistent with metastatic disease. It is important to adequately sample these lesions to determine whether or not they contain malignant elements.
C. Medical Intervention for Epithelial Ovarian Cancer
After the initial surgical intervention and definitive staging, subsequent treatment can be established. Almost all patients with EOC will receive chemotherapy. The 1 exception is for stage IA disease and grade 1 tumors, where a discussion of the risks and benefits of chemotherapy should be undertaken because chemotherapy after the initial surgical treatment may have no influence on survival. For all other stages, chemotherapy is indicated. Agents shown to be active against EOC include cisplatin, carboplatin, cyclophosphamide, and paclitaxel. Combination therapies have been demonstrated to be superior to single-agent treatment. Typically, chemotherapy is started 4–6 weeks after surgical intervention. Earlier administration has not been shown to provide a benefit.
Currently the most effective regimen uses a combination of paclitaxel and carboplatin. This combination has replaced the former treatment with cyclophosphamide and cisplatin because it was shown to be more efficacious in a number of clinical trials. A typical regimen includes systemic administration of carboplatin and paclitaxel for 6 cycles at 3-week intervals. Potential toxicities of this treatment include nausea, vomiting, diarrhea, alopecia, nephrotoxicity, and myelo-suppression (see Chapter 52).
Carboplatin is a second-generation platinum analogue that shows clinical efficacies and survival rates similar to cisplatin when used in combination with paclitaxel. However, the frequency of gastrointestinal side effects and neurotoxicity associated with carboplatin was found to be lower compared to cisplatin.
The route of administration may vary depending on the stage. Patients with optimally cytoreduced stage III EOC are offered intraperitoneal (IP) or systemic intravenous (IV) administration of the chemotherapeutic agents. The IP route has been shown to increase survival, although an increase in side effects is also noted. For patients with suboptimally cytoreduced disease or stage IV disease, systemic IV administration is the preferred route.
Occasionally, chemotherapy will be offered in patients with stage IV disease prior to surgical staging. This is termed neoadjuvant chemotherapy and may be useful to lessen the tumor burden, thereby decreasing the morbidities associated with surgical resection of advanced disease. It may also increase the chance of optimal debulking.
Assessment of response to combination chemotherapy is based on physical examination, changes in size of palpable or radiographically measurable lesions, and changes in the CA-125 level. Although the preoperative CA-125 level does not correlate with tumor burden, changes in response to chemotherapy appear to be of some prognostic benefit. An elevated CA-125 (>35 IU/mL) predicts persistent disease at second look in more than 97% of patients. However, a normal CA-125 level does not completely exclude the possibility of residual, subclinical disease.
Most patients develop resistance to platinum-based regimens during the course of treatment. Salvage therapy for ovarian cancer is rarely curative, although significant prolongation of survival may be achieved in some instances. The response to re-treatment with platinum-based chemotherapy is influenced by the time interval between completion of the initial regimen and subsequent disease recurrence: The greater the interval, the greater is the likelihood of a beneficial response, with platinum resistance defined as recurrence <6 months after completion of combination chemotherapy or progression on treatment.
D. Medical Intervention for Germ Cell Neoplasms
Significant advances have been made in the treatment of germ cell neoplasms of the ovary. Once associated with 5-year survival rates of <20–30%, these neoplasms are now considered curable in a majority of cases following the introduction and refinement of combination chemotherapy.
Dysgerminoma is the most radiation-sensitive neoplasm identified. Historically, it has been treated with whole abdominal radiation therapy with excellent results. More recently, chemotherapy with cisplatin-containing regimens has been administered with excellent results. A significant advantage of chemotherapy is the potential to preserve future reproductive potential compared with radiation therapy.
The other germ cell neoplasms are rare, and the optimal chemotherapy and duration of therapy have not been established. Regimens such as vinblastine/bleomycin/cisplatin, vincristine/dactinomycin/cyclophosphamide, and bleomycin/etoposide/cisplatin have been used with encouraging results. Response to chemotherapy is based on physical examination and the decrease in serum tumor markers, if initially elevated.
E. Radiation Therapy
With respect to germ cell neoplasms, radiation therapy has been used successfully in the treatment of patients with dysgerminoma. For patients with EOC, radiation therapy plays a limited role mainly because of radiation damage to the small bowel, liver, and kidneys. Radioisotopes such as intraperitoneal phosphorus-32 may be of benefit in patients with stage IC disease and those with microscopically positive second-look operations.
F. Intervention for Fallopian Tube Cancers
The surgical therapy of fallopian tube carcinoma is the same as that recommended for EOC. In addition, the same type of surgical staging should be performed if for no other reason than it is often not clear at the time of surgery whether the primary cancer is of ovarian or fallopian tube origin. The staging system for ovarian cancer is often applied to neoplasms of the fallopian tube, although this is by custom rather than FIGO recommendations.
Chemotherapy for fallopian tube cancer has evolved along the same lines as that for EOC. The currently used chemotherapeutic regimen is similar to that of EOC and includes platinum combination chemotherapy. Radiation may also be used in select cases with no residual disease after surgery. Because there are little data on well-staged tubal lesions, it is unclear if patients with early-stage disease benefit from adjuvant therapy.
G. Alternative Therapies
A number of alternative therapies have been applied for the treatment of EOC. Cytokines like interleukin-2 and interferon-γ, either alone or in combination with chemotherapy, have shown some promising effects. Monoclonal antibodies directed against ovarian cancer–associated antigens, including CA-125, HMFG (human milk-fat globulin), and HER-2/neu, have been used with variable clinical responses. Recently, antibodies against vascular endothelial growth factor (VEGF) have shown efficacy in patients with ovarian cancer. Anti-VEGF antibodies are currently being tested in combination with carboplatin and paclitaxel in first-line chemotherapy for ovarian cancer patients. Gene therapy trials have used different antitumor approaches, including the delivery of tumor suppressor gene p53 via recombinant adenovirus into the peritoneal cavities. The early trials have not shown significant clinical response, mainly as a result of the inefficiency of intraperitoneal and intratumoral gene transfer.
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Prognosis
Ovarian cancer is the second most common gynecologic malignancy, yet the most common cause of death in women with such a malignancy. The prognosis for patients with ovarian cancer is primarily related to the stage of disease (Table 50–8). Within each stage of disease, other factors such as cell type and response to chemotherapy are also important in determining disease-free survival and overall survival. In general, patients with well-differentiated, diploid neoplasms with an S-phase fraction of <8–10% do better than patients who have poorly differentiated, aneuploid, rapidly proliferating (eg, high S-phase fraction) neoplasms.
Table 50–8. Overall survival rates for patients with epithelial ovarian cancer.
In general, germ cell tumors are associated with better 5-year survival rates than epithelial ovarian neoplasms. Patients with dysgerminoma have a 5-year survival rate of 95%. Immature teratomas are associated with 5-year survival rates of 70–80%. An endodermal sinus tumor is associated with a 5-year survival rate of 60–70%. Embryonal carcinoma, choriocarcinoma, and polyembryoma are very rare lesions, and it is difficult to assess 5-year survival estimates. Epithelial ovarian neoplasms of low malignancy potential are characterized by 5-year survival rates of 95%, reflecting their protracted and indolent biologic behavior.
The prognosis for patients with fallopian tube carcinoma is based on the stage of disease. The overall 5-year survival rate is approximately 56%. The prognosis for early-stage disease is much better than for advanced disease, as 5-year survival is 84% with stage I disease, 52% with stage II, and 36% with stage III.